Although therapeutics for treating posterior segment eye diseases are emerging, the treatment of these diseases is limited to a significant extent by the difficulty of delivering effective dose of therapeutics to the target tissues. This is because the eye is a well-protected organ that possesses several barriers for deterring foreign substances from entering the posterior segment of the eye. In addition, many promising therapeutics for treating posterior segment eye diseases, such as PEGylated-aptamer (Macugen®) and antibody fragments (Lucentis®), have high molecular weight, and thus can hardly diffuse across the ocular tissues. Therefore, an effective, non-invasive method for delivering macromolecules to the posterior segment of the eye is needed.
Common routes for delivering ocular therapeutics to the posterior segment of the eye include: the intravitreal route, the systemic route, the transcorneal route, the periocular route, and the transscleral route. The intravitreal route, where therapeutic agents are directly injected into the vitreous of the eye, is the most direct and effective, but is also the most invasive route. In addition to the risk of damaging the ocular tissues, the mobility of large molecules, particular positively charged ones, is restricted in the vitreous. As a result, large molecules can hardly diffuse from the vitreous to the retina. (1) Furthermore, as multiple injections are frequently required, there is a risk of having cataract, retinal detachment, vitreous hemorrhage and endophthalmitis after treatment. (18)
Systemic delivery, another way to deliver drugs to the posterior segment, also has significant limitations. A large systemic dose is necessary to reach the therapeutic level because the blood-retinal barrier (BRB) largely decreases the flux of drugs to the retina. Undesirable side effects are resulted when a high concentration of therapeutics is distributed in the body via the circulation system. (16) In addition, emerging therapeutics such as proteins and nucleic acids may be degraded during systemic delivery before they reach the eye.
Topical application using eye drops takes the transcorneal route. Despite the ease of administration, drug delivery via this route has to overcome a number of difficult barriers and undertake a long path until drugs finally reach the posterior segment. Before entering the anterior segment, however, drug molecules may have already been eliminated by solution drainage, lacrimation and tear dilution, tear turnover, and conjunctival adsorption, or blocked by the tight junctions in the corneal epithelium. (2, 3) Even after reaching the anterior segment, therapeutics may still be removed by the intraocular tissues and fluids. The iridolenticular diaphragm and the aqueous humor flow would also prevent the therapeutics from entering the posterior segment. (4, 5) As a result, only 3% of the administered dose eventually enters the aqueous humor in the anterior segment, (15) and there is almost no therapeutics delivered into the posterior segment via the topical route.
Periocular injection is performed by injecting drugs in the periocular space of the eye. After injection, the drugs diffuse down their concentration gradient across the sclera into the posterior segment of the eye. One limitation of this approach is the difficulty of maintaining a high concentration gradient to deliver therapeutics into the eye. In addition, safety of periocular injection relies on high levels of medical skills. Further, as multiple injections are frequently needed for long-term treatment, the risk of retinal detachment, cataract formation and other ocular maladies increases. (17)
Transscleral route has attracted much interest as a potential path for delivering therapeutics into the posterior segment, because there are certain advantages: first, diffusion of macromolecules through the sclera is feasible, as demonstrated in the ex viva diffusion experiments using rabbit sclera by Ambati et al. (24) Second, the distance for drug molecules to penetrate into the posterior segment is shorter via the transscleral than the transcorneal route. After diffusing through the sclera, drug molecules are closer to the vicinity where most posterior diseases occur: the choroid and the retina.
In the transscleral route, the sclera is the first and outmost barrier. Although by passive diffusion, macromolecules like proteins are able to pass through the sclera (6), the permeability is low and the macromolecules can be easily washed away by tears or blood flow in the conjunctiva and the episclera. (7) As a result, the concentration gradient across the sclera and thus the flux of macromolecules into the intraocular tissue decreases dramatically.
A less invasive method has been developed by Jiang et al., using microneedles to deliver soluble molecules, nanoparticles and microparticles intrasclerally. (25) Using this approach, controlled drug release within the sclera was made possible by delivering drug-encapsulated nanoparticles and microparticles into the deeper sclera. Drug molecules could then diffuse to the neighboring posterior ocular tissues. Another technique, transscleral iontophoresis, has been employed by a number of research groups to deliver drugs to the posterior segment using electric field. (26-28) However, iontophoresis is limited to charged drugs. (17, 29, 20 Patients also complained about the burning sensation. (31) Another approach is scleral/intrascleral implant, which is capable of providing a prolonged therapeutic action, thereby solving the problem of multiple injections. However, one limitation is that implants require surgery and often cause discomfort.
Ultrasound, a longitudinal wave which has frequency above audible range, is a well-known technology in the medical field. It has been applied for diagnostic purposes, for example, for measuring the intraocular pressure of eye, and for therapeutic uses, for example, in healing muscle damage and in disrupting the lens in cataract surgery. Ultrasound, especially low-frequency ultrasound, has also been explored in enhancing drug delivery in transdermal route. It is found that the cavitation effect of the ultrasound would disrupt the outermost layer of the skin temperorily to increase the permeability of the skin. Mitragotri et al. has successfully delivered insulin and other protein molecules across human skin using low frequency ultrasound. (9) In clinical studies, methylprednisolone, cyclosporin and eutectic mixture of local anesthetics (EMLA) have been successfully delivered to produce significant therapeutic effects. (10, 11)
However, limited research has been performed to use ultrasound in ocular drug delivery. The most relevant research using ultrasound on ocular drug delivery is the ultrasound-mediated transconreal drug delivery. It has been discovered that ultrasound can enhance delivery of sodium fluorescein (a low molecular weight compound) through the cornea for ten times than passive diffusion. (12-14) To the best of our knowledge, none has investigated the effects of ultrasound in delivering macromolecules via the transscleral route.
The prior art of ocular drug delivery to the posterior segment of the eye is either ineffective or invasive and causes side effects. Therefore, a substantial need exists for a non-invasive, safer and more effective system and method for intrascleral delivery of macromolecules.